1. Be able to recognize and distinguish the following Mendelian patterns of inheritance in a pedigree: (a) Y-linked, (b) co-dominant. Students will be expected to apply this knowledge to correctly solved genetic problems. (p.469, 470)
Co-dominant Traits
When both alleles are expressed in heterozygotes with an intermediate level of gene products or both gene products produced. Example: ABO or MN blood type loci.
Y-linked Inheritance
Only males are affected and only transmited from father to son (gender bias and transmission bias). Y-chromosome has very few genes (less than 50) and contain small highly homologous regions near the termini of long and short arms called pseudoautosomal regions that can undergo recombination during meiosis. Known Y-linked genes: testis determinating factor (SRY, TDF), tooth size, height influencing gene, spermatogenesis (azoospermia) factors, and hair ears.
2. Be able to define and categorize how the following phenomenon can complicate the interpretation of pedigrees: (a) epistasis, (b) genetic heterogeneity, (c) pleiotrophy, (d) penetrance, (e) variable degrees of expression, (f) sex-influenced/sex-limited traits, (g) phenocopy, (h) mosaicism. (p.472, 475, 477, 479, 480)
Epistasis
Non-allelic gene-gene interactions that modify expression of a trait -- when one gene modifies the effect of another. Can be penetrance (all-or-none) of variable expression (shades of grey).
Genetic Heterogeneity
Allelic heterogenoeity (Different Alleles) -- different mutations at the same locus that result in similar phenotype but perhaps differing in extent/severity because of allelic differences. i.e., different alleles for phenylalanine hydroxylase that result in varying severity of hyperphenylalaninemia.
Locus heterogeneity (Different Loci) -- Mutations at different loci (different genes) result in a similar phenotype. These genes may be located on different chromosomes and may be expressed in different cell types/tissues. THye can manifest multiple modes of inheritance.
Pleiotrophy
When a mutation in a single gene has multiple manifestations in different tissues. i.e., one gene affecting multiple phenotypes.
Penetrance
When all individuals having the same mutant genotype do not all express the mutant phenotype. This is an all-or-none phenomenon with individuals either expressing or not expressing the mutant phenotype despite all having the mutant genotype.
Variable Degrees of Expression
When there is large variation in the expression of a mutant phenotype between affected individuals with the same genotype. This is a shades-of-grey phenomenon with individuals presenting with varying severities, extensiveness, etc. of the mutant phenotype.
Sex-influence/limited Traits
Sex-influenced traits -- mode of trait expression is modified by the gender of the individual. i.e., male pattern baldness is manifested as a dominant trait in males but behaves recessively in females.
Sex-limited traits -- expression of an autosomal trait that is limited to one gender. i.e., prostate cancer.
Phenocopy
Environmental influences lead to manifestations that mimick a genetic disorder. i.e., genetic disorder phocomelia and thalidomide-induced abnormalities.
Mosaicism
Presence of two or more distinct cell lines in an individual.
Somatic Mosaicism -- event bringing about mosaic condition occured post-zygotically and abnormal phenotype cannot be inherited.
Germline Mosaicism -- abnormal cell line is present only in the gonads and is responsible for the recurrance of a dominant phenotype when neither parent is affected. Most commonly recognized in connective tissue diseases.
3. Be able to describe how genotype x environment interactions can affect inheritance of traits. (p.477, 494)
Genotype x environment can alter the expression of disease phenotype. i.e., restriction of dietary phenylalanine in newborns with phenylketouria can prevent mental retardation.
4. Be able to describe the influence of genetic background on the phenotypic expression of a genotype. (p.475)
Genetic background differences can result in different manifestations of phenotype resulting in varibale expressivity. The genetic variability can result from alleic and locus heterogeneity.
5. Be able to describe the characteristics of (a) threshold traits and (b) traits showing additive inheritance and apply these to answering questions dealing with multifactorial and quantitative traits. (p.487, 490)
Threshold traits and additive traits are the two major modes of quantitiative inheritance.
Threshold Traits
Phenotypes are discontinuous, either being present or absent, and recurrence risks represent average risks and will vary among different families with increasing risk with increasing affected relatives and severity of malformation/disease. Individuals are affected when genetic predisposition reaches above a certain value as determined by genetic and environmental components.
Genetic compoonent shifts the frequency/genetic liability curve while the threshold remains the same; the closer the relationship, the further the shift.
Environmental component shifts the threshold but not the frequency/genetic liability curve (distribution).
When sex ratio of affected progeny is significantly skewed, offspring of affected probands of less frequently affected sex have a higher relative risk.
Additive Inheritance
Multiple genes control a specific phenotype and operate additively to generate the final phenotypic result. The result is that phenotypes are continuous, resulting in a distribution of different phenotypes in a population. i.e. height.
6. Be able to describe the differences between simple mendelian inheritance and multifactorial inheritance and to compare how quantitative traits controlled by polygenic inheritance, as opposed to Mendelian traits, will behave in breeding experiments. (p.481)
Multifactorial inheritance referes to multiple environmental factors with multiple genes interacting to produce a phenotypic trait.
Characteristics of Multifactorial Inheritance:
1. Do not demonstrate simple, Mendelian pattern of inheritance (no single gene errors).
2. Demonstrate familial aggregation -- relatives of an affected individual are more likely to share disease-predisposing allels in common with the affected person compared to unrelated individuals.
3. Pairs of relatives who share disease predisposing genotypes at relavant loci may still be discordant for phenotype (showing incomplete penetrance) because of non-genetic factors in disease causation.
4. Disease is more common in close relatives of a proband, compared to relatives less closely related to the proband.
7. Be able to describe the formual used to calculate heritability. Sutdents should be able to describe how alterations in the variance components in this formula will affect heritability. (p.485)
Variance is the sum of the squares of the difference between each value in a distribution and the mean value. yay for statistics!
Ve = environmental variance
Vg = genetic variance
Vt = Total variance
Vt = Vg + Ve
Heritability = Vg / Vt
Therefore, Heritability = Vg / (Vg + Ve)
As Ve increases, heritability must decrease accordingly. Brilliant!
8. Be able to describe how polygenic traits behave in (a) family studies, (b) adoption studies, (c) twin studies. (p.486)
Correlations between individuals can be determined for polygenic traits. Example: blood pressure.
(a) family studies -- show some correlation between parent and child for developing blood pressure
(b) adoption studies -- no correlation between adopted child and adopted child for developing disease; no genetic relationship, only shared envirnonment)
(c) Twin studies -- correlation between dizygotic twins (genetically similar, shared environment) has greater variation than monozygotic twins (genetically identical, shared environment). Supports genetic component for blood pressure in humans.
For polygenic traits, the likelihood that both monozygotic twins will be affected is signficantly less than 100% but still much greater than the chance that both dizygotic twins will be affected (usually range 20-40%).
Objectives
1. Be able to recognize and distinguish the following Mendelian patterns of inheritance in a pedigree: (a) Y-linked, (b) co-dominant. Students will be expected to apply this knowledge to correctly solved genetic problems. (p.469, 470)
Co-dominant Traits
When both alleles are expressed in heterozygotes with an intermediate level of gene products or both gene products produced. Example: ABO or MN blood type loci.
Y-linked Inheritance
Only males are affected and only transmited from father to son (gender bias and transmission bias). Y-chromosome has very few genes (less than 50) and contain small highly homologous regions near the termini of long and short arms called pseudoautosomal regions that can undergo recombination during meiosis. Known Y-linked genes: testis determinating factor (SRY, TDF), tooth size, height influencing gene, spermatogenesis (azoospermia) factors, and hair ears.
2. Be able to define and categorize how the following phenomenon can complicate the interpretation of pedigrees: (a) epistasis, (b) genetic heterogeneity, (c) pleiotrophy, (d) penetrance, (e) variable degrees of expression, (f) sex-influenced/sex-limited traits, (g) phenocopy, (h) mosaicism. (p.472, 475, 477, 479, 480)
Epistasis
Non-allelic gene-gene interactions that modify expression of a trait -- when one gene modifies the effect of another. Can be penetrance (all-or-none) of variable expression (shades of grey).
Genetic Heterogeneity
Allelic heterogenoeity (Different Alleles) -- different mutations at the same locus that result in similar phenotype but perhaps differing in extent/severity because of allelic differences. i.e., different alleles for phenylalanine hydroxylase that result in varying severity of hyperphenylalaninemia.
Locus heterogeneity (Different Loci) -- Mutations at different loci (different genes) result in a similar phenotype. These genes may be located on different chromosomes and may be expressed in different cell types/tissues. THye can manifest multiple modes of inheritance.
Pleiotrophy
When a mutation in a single gene has multiple manifestations in different tissues. i.e., one gene affecting multiple phenotypes.
Penetrance
When all individuals having the same mutant genotype do not all express the mutant phenotype. This is an all-or-none phenomenon with individuals either expressing or not expressing the mutant phenotype despite all having the mutant genotype.
Variable Degrees of Expression
When there is large variation in the expression of a mutant phenotype between affected individuals with the same genotype. This is a shades-of-grey phenomenon with individuals presenting with varying severities, extensiveness, etc. of the mutant phenotype.
Sex-influence/limited Traits
Sex-influenced traits -- mode of trait expression is modified by the gender of the individual. i.e., male pattern baldness is manifested as a dominant trait in males but behaves recessively in females.
Sex-limited traits -- expression of an autosomal trait that is limited to one gender. i.e., prostate cancer.
Phenocopy
Environmental influences lead to manifestations that mimick a genetic disorder. i.e., genetic disorder phocomelia and thalidomide-induced abnormalities.
Mosaicism
Presence of two or more distinct cell lines in an individual.
Somatic Mosaicism -- event bringing about mosaic condition occured post-zygotically and abnormal phenotype cannot be inherited.
Germline Mosaicism -- abnormal cell line is present only in the gonads and is responsible for the recurrance of a dominant phenotype when neither parent is affected. Most commonly recognized in connective tissue diseases.
3. Be able to describe how genotype x environment interactions can affect inheritance of traits. (p.477, 494)
Genotype x environment can alter the expression of disease phenotype. i.e., restriction of dietary phenylalanine in newborns with phenylketouria can prevent mental retardation.
4. Be able to describe the influence of genetic background on the phenotypic expression of a genotype. (p.475)
Genetic background differences can result in different manifestations of phenotype resulting in varibale expressivity. The genetic variability can result from alleic and locus heterogeneity.
5. Be able to describe the characteristics of (a) threshold traits and (b) traits showing additive inheritance and apply these to answering questions dealing with multifactorial and quantitative traits. (p.487, 490)
Threshold traits and additive traits are the two major modes of quantitiative inheritance.
Threshold Traits
Phenotypes are discontinuous, either being present or absent, and recurrence risks represent average risks and will vary among different families with increasing risk with increasing affected relatives and severity of malformation/disease. Individuals are affected when genetic predisposition reaches above a certain value as determined by genetic and environmental components.
Genetic compoonent shifts the frequency/genetic liability curve while the threshold remains the same; the closer the relationship, the further the shift.
Environmental component shifts the threshold but not the frequency/genetic liability curve (distribution).
When sex ratio of affected progeny is significantly skewed, offspring of affected probands of less frequently affected sex have a higher relative risk.
Additive Inheritance
Multiple genes control a specific phenotype and operate additively to generate the final phenotypic result. The result is that phenotypes are continuous, resulting in a distribution of different phenotypes in a population. i.e. height.
6. Be able to describe the differences between simple mendelian inheritance and multifactorial inheritance and to compare how quantitative traits controlled by polygenic inheritance, as opposed to Mendelian traits, will behave in breeding experiments. (p.481)
Multifactorial inheritance referes to multiple environmental factors with multiple genes interacting to produce a phenotypic trait.
Characteristics of Multifactorial Inheritance:
1. Do not demonstrate simple, Mendelian pattern of inheritance (no single gene errors).
2. Demonstrate familial aggregation -- relatives of an affected individual are more likely to share disease-predisposing allels in common with the affected person compared to unrelated individuals.
3. Pairs of relatives who share disease predisposing genotypes at relavant loci may still be discordant for phenotype (showing incomplete penetrance) because of non-genetic factors in disease causation.
4. Disease is more common in close relatives of a proband, compared to relatives less closely related to the proband.
7. Be able to describe the formual used to calculate heritability. Sutdents should be able to describe how alterations in the variance components in this formula will affect heritability. (p.485)
Variance is the sum of the squares of the difference between each value in a distribution and the mean value. yay for statistics!
Ve = environmental variance
Vg = genetic variance
Vt = Total variance
Vt = Vg + Ve
Heritability = Vg / Vt
Therefore, Heritability = Vg / (Vg + Ve)
As Ve increases, heritability must decrease accordingly. Brilliant!
8. Be able to describe how polygenic traits behave in (a) family studies, (b) adoption studies, (c) twin studies. (p.486)
Correlations between individuals can be determined for polygenic traits. Example: blood pressure.
(a) family studies -- show some correlation between parent and child for developing blood pressure
(b) adoption studies -- no correlation between adopted child and adopted child for developing disease; no genetic relationship, only shared envirnonment)
(c) Twin studies -- correlation between dizygotic twins (genetically similar, shared environment) has greater variation than monozygotic twins (genetically identical, shared environment). Supports genetic component for blood pressure in humans.
For polygenic traits, the likelihood that both monozygotic twins will be affected is signficantly less than 100% but still much greater than the chance that both dizygotic twins will be affected (usually range 20-40%).